BACKGROUND Arsenic trioxide induces growth inhibition and apoptosis in human melanoma cell lines. Therefore, a Phase II trial was conducted to evaluate the efficacy and toxicity of single‐agent arsenic trioxide in patients with Stage IV melanoma. METHODS Twenty patients, 10 with metastatic melanoma of cutaneous origin and 10 with metastatic melanoma of choroidal origin, received arsenic trioxide 0.25 mg/kg/day for 5 days, followed by a maintenance dose of 0.35 mg/kg/day twice a week. All patients with melanoma of cutaneous origin and four patients with melanoma of choroidal origin had received prior therapy. RESULTS Single‐agent arsenic trioxide did not induce clinical response in this patient population. Eight patients (five with melanoma of cutaneous origin, and three with melanoma of choroidal origin) had disease stabilization for at least six weeks. The median overall survival duration for patients with melanoma of cutaneous origin was 7.9 months, and that of patients with melanoma of choroidal origin has not been reached at a median follow‐up duration of 11.8 months. Grade 3 toxicity included neutropenia, fatigue, abdominal pain, and arthralgia. Grade 4 toxicity did not occur. CONCLUSIONS Single‐agent arsenic trioxide was generally well tolerated; however, no tumor regression was observed in this patient population. Future clinical trials should evaluate arsenic trioxide in combination with other anticancer drugs that may improve its clinical activity in melanoma. Cancer 2005. © 2005 American Cancer Society. The authors conducted a Phase II trial on 20 patients to evaluate efficacy and toxicity of single‐agent arsenic trioxide in patients with Stage IV melanoma. Single‐agent arsenic trioxide did not induce clinical response in this patient population.